tbuckley/cabot-search huggingface dataset:
Abstract 3580: Integrative genomics of checkpoint blockade response in advanced non-small cell lung cancer
Authors: Arvind Ravi, Justin Gainor, Monica Arniella, Chip Stewart, Sam Freeman, Mark M. Awad, Patrick Forde, Valsamo Anagnostou, Brian Henick, Jonathan W. Riess, Don Gibbons, Nathan Pennell, Vamisdhar Velcheti, Ignaty Leshchiner, Jaegil Kim, Subba Digumarthy, Mari Mino-Kenudson, John Heymach, Natalie Vokes, Andrew Griffin, Biagio Ricciuti, Naiyer Rizvi, Roy Herbst, Victor Velculescu, Julie Brahmer, Kurt Schalper, Pasi Janne, Jedd Wolchok, Alice Shaw, Nir Hacohen, Gad Getz, Matthew D. Hellmann
Journal: Cancer Research (2022)

Abstract The introduction of checkpoint blockade therapy, specifically anti-PD-1/PD-L1 agents, has transformed the treatment landscape of advanced Non-Small Cell Lung Cancer (NSCLC). While our understanding of the biology underlying immunotherapy in NSCLC is still incomplete, studies to date have established central roles for Tumor Mutation Burden (TMB) and PD-L1 Tumor Proportion Score (PDL1-TPS). In order to expand our understanding of the molecular features underlying response in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer-Mark Foundation (SU2C-MARK) Cohort, a collection of 393 patients with whole exome and/or RNA sequencing along with matched checkpoint blockade response annotation. We identify a number of significant associations between molecular features and response, including: 1) favorable and unfavorable genomic subgroups; 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activated (favorable) microenvironments; and 3) a novel de-differentiated tumor-intrinsic subtype characterized by high TMB, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC. Citation Format: Arvind Ravi, Justin Gainor, Monica Arniella, Chip Stewart, Sam Freeman, Mark M. Awad, Patrick Forde, Valsamo Anagnostou, Brian Henick, Jonathan W. Riess, Don Gibbons, Nathan Pennell, Vamisdhar Velcheti, Ignaty Leshchiner, Jaegil Kim, Subba Digumarthy, Mari Mino-Kenudson, John Heymach, Natalie Vokes, Andrew Griffin, Biagio Ricciuti, Naiyer Rizvi, Roy Herbst, Victor Velculescu, Julie Brahmer, Kurt Schalper, Pasi Janne, Jedd Wolchok, Alice Shaw, Nir Hacohen, Gad Getz, Matthew D. Hellmann. Integrative genomics of checkpoint blockade response in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3580.
Abstract 3156: Tumor Treating Fields reduce cellular survival of human mesenchymal stromal cells via apoptosis and senescence induction
Authors: Alexander Rühle, Maren Strack, Anca-Ligia Grosu, Nils H. Nicolay
Journal: Cancer Research (2022)

Abstract Background Tumor Treating Fields (TTFields), alternating electric fields with intermediate field intensity, have shown clinical efficacy in several tumor entities, leading to clinical approval for glioblastoma and mesothelioma treatment. As mesenchymal stromal cells (MSCs) belong to the tumor microenvironment and exhibit - depending on the tumor type and microenvironment - either pro-tumorigenic or anti-tumorigenic abilities, we aimed to study the effects of TTFields on human MSCs. Methods Human MSCs were isolated from the bone marrow of three different healthy donors and were exposed to TTFields for 72 hours. MSCs’ clonogenic survival, proliferation and viability was analyzed after different TTFields frequencies. Boyden chamber assays were carried out to investigate the influence of TTFields on the migratory potential of MSCs. Flow cytometry analyses of caspase-3 and annexin V were conducted to determine MSCs’ apoptosis rates after TTFields treatment. TTFields-induced senescence was quantified using beta-galactosidase stainings. MSCs’ characteristic surface marker expression (CD73, CD90 and CD105) was studied after TTFields treatment. Result TTFields led to significantly reduced clonogenic survival (70-90% reduction compared to controls) and cellular proliferation (approximately 50% reduction) in all analyzed MSC specimens. However, MSCs’ metabolic viability was largely unaffected after TTFields exposure. Within a range between 100 and 500 kHz, there was no frequency dependence of TTFields’ anti-proliferative effect on human MSCs. As determined by Bodyen Chamber assays, TTFields resulted in a considerable reduction of MSCs’ migratory potential. TTFields increased both cellular apoptosis and senescence in all MSC samples, whereas there was no alteration of MSCs’ characteristic surface marker pattern. Conclusion As TTFields considerably reduce MSCs’ survival and migratory potential, TTFields could attenuate the pro-tumorigenic effects of tumor-associated MSCs that were recently described in glioblastoma patients. Co-culture experiments of MSCs and tumor cells after TTFields treatment as well as in vivo experiments are planned in the future. Citation Format: Alexander Rühle, Maren Strack, Anca-Ligia Grosu, Nils H. Nicolay. Tumor Treating Fields reduce cellular survival of human mesenchymal stromal cells via apoptosis and senescence induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3156.
Abstract 2997: Combination treatment with cIAP and WEE1 inhibitors exhibits synergism in HPV-positive and HPV-negative head and neck squamous carcinoma cells
Authors: Tiffany Toni, Ethan Morgan, Ramya Viswanathan, Xinping Yang, Hui Cheng, Carter Van Waes
Journal: Cancer Research (2022)

Abstract Head and neck squamous cell carcinoma (HNSCC) remains a lethal and prevalent diagnosis with limited treatment options for recurrent metastatic cases, particularly in patients with sporadic, human papillomavirus (HPV) negative disease. Recently, the Human Cancer Genome Project identified cell death and NF-κB signaling alterations in a subset of HPV- and HPV+ HNSCC. Co-amplification of Fas-associated death domain (FADD) and cellular inhibitor of apoptosis protein 1 (cIAP1) was identified in HPV- HNSCC, whereas Tumor Necrosis Factor receptor-associated factor 3 (TRAF3) deletion was linked with HPV+ HNSCC. Birinapant, a cIAP inhibitor with primary affinity for cIAP1, functions as a SMAC mimetic to modulate downstream TNF death signaling and promote apoptosis. Clinical trials with Birinapant have demonstrated tolerability and favorable pharmacokinetics but limited activity as a single agent. Our lab recently demonstrated a key interaction between TNF-NF-κB signaling and the G2/M checkpoint kinase WEE1, providing a possible rationale for combination treatment targeting these pathways. We hypothesize that dual-antagonist therapy has the potential to synergistically inhibit TNF-induced canonical NF- κB pro-survival signaling, while enhancing sensitization to TNF-caspase and G2/M mitotic cell death. To investigate this, in vitro studies of Birinapant in combination with Adavosertib, a potent WEE1 inhibitor, were performed. Birinapant and Adavosertib demonstrated drug synergism to varying degrees in all HPV- and HPV+ cell lines tested, both in the presence and absence of tumor necrosis factor alpha (TNF-α), according to the Chou-Talalay method. In the majority of cell lines, synergistic drug activity, as indicated by a low combination index, was positively correlated with percent inhibition. These results were confirmed by increased levels of apoptosis as demonstrated by flow cytometry and both early and sustained cell growth inhibition over time in impedance assays. Ongoing studies include additional characterization of the downstream effects of these agents on NF-κB pro-survival signaling and the cell cycle, along with evaluation in a preclinical murine xenograft model with combined radiotherapy. Citation Format: Tiffany Toni, Ethan Morgan, Ramya Viswanathan, Xinping Yang, Hui Cheng, Carter Van Waes. Combination treatment with cIAP and WEE1 inhibitors exhibits synergism in HPV-positive and HPV-negative head and neck squamous carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2997.
Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor–Positive Breast Cancer
Authors: Youli Xia, Xiaping He, Lorna Renshaw, Carlos Martinez-Perez, Charlene Kay, Mark Gray, James Meehan, Joel S. Parker, Charles M. Perou, Lisa A. Carey, J. Michael Dixon, Arran Turnbull
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor–positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors. Experimental Design: We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor–positive breast cancer treated with neoadjuvant then adjuvant endocrine therapy; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received two or more lines of endocrine therapy, with subsequent treatment lines being initiated at the time of development of resistance to the previous endocrine therapy. DNA whole-exome sequencing and RNA sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR. Results: Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared with paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS, and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms. Conclusions: The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient.
Abstract 3520: Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma
Authors: Daniella Vaskovich-Koubi, Ron kleiner, Anat Eldar-Boock, Sabina Pozzi, Dikla Dikla Ben-Shushan, Helena F. Florindo, Ronit Satchi-Fainaro
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death. Low response rate, acquired resistance, severe side effects, highly desmoplastic, and immunosuppressive microenvironment have limited the clinical outcomes of immunotherapy in PDAC. To overcome these hurdles, we set to design novel immunotherapy that would be safe, efficacious, and selective to PDAC. The failure of immunotherapies to yield clinical response in PDAC is partially attributed to the inefficient antigen presentation by dendritic cells (DC) which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). DC have an important role in the initiation and regulation of the innate and adaptive immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Trp53R172H is among the most common TP53 mutations in human PDAC, and is known as one of PDAC TAA. Despite the poor clinical outcomes, longer survival time was observed in PDAC patients with tumors that express high number of TAA combined with an abundant presentation of CD8+ T cell. To that end, we designed a DC-targeted nanoparticle (NP) containing PDAC Trp53R172H TAA and immune potentiators, with the DC targeting moiety, mannose, that was covalently conjugated to the NP, to enhance TAA presentation on DC. Thus, promote specific activation of T cells against PDAC’s TAA. The therapeutic activity of the NP was evaluated in vitro by our newly established 3D PDAC spheroids model, which composed of freshly isolated murine stromal cells, therefore, better imitates the complex microenvironment found in PDAC in vitro. Along with an in vivo PDAC model, we evaluated the safety profile and therapeutic effect of our NP. The NP proposed herein successfully activated splenocytes and induced a specific cytotoxic reaction against PDAC cells ex vivo, which may result in an improved survival rate. Citation Format: Daniella Vaskovich-Koubi, Ron kleiner, Anat Eldar-Boock, Sabina Pozzi, Dikla Dikla Ben-Shushan, Helena F. Florindo, Ronit Satchi-Fainaro. Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3520.
Abstract LB538: Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC
Authors: Qinglin Du, Wengang Zeng, Xueyan Yang, Liwen Liang, Xueqin Li, Yan Li, Yiqi Cao, Zongjun Xia, Jing Zhang, Qian Ding, Shuhua Han
Journal: Cancer Research (2022)

Abstract Background: The EGFR tyrosine kinase inhibitors (TKIs) have been effectively used for non-small cell lung cancer (NSCLC) driven by EGFR mutations. However, patients eventually develop drug resistance via various mechanisms such as secondary EGFR mutations and activation of alternative pathways. The cMET amplification is one of the resistant mechanisms. Amivantamab, a bispecific antibody to EGFR/c-Met has shown that concurrent inhibition of EGFR and c-Met can overcome resistance of EGFR-TKIs and improve patient outcomes. Thus, amivantamab has been approved for the treatment of advanced NSCLC patients with EGFR exon20ins mutations in the US. GB263T is a novel EGFR/cMET/cMET tri-specific antibody with enhanced ADCC function. The current study has demonstrated GB263T exhibited robust anti-tumor activity by in vitro and in vivo studies. Methods: GB263T has been extensively characterized. The binding/blocking activities were analyzed by SPR and ELISA. The protein levels and phosphorylation of EGFR/cMET were detected by Western Blot. Internalization ability was evaluated by confocal microscope. ADCC function was tested by Jurkat-CD16A-NFAT-Luc reporter system. Various CDX and PDX models were used to evaluate the in vivo efficacy in tumor inhibition. Results: GB263T showed high affinity binding to EGFR and cMET, with robust blocking activity. Moreover, GB263T induced receptor internalization and EGFR/cMET phosphorylation in NSCLC cell lines. GB263T dose-dependently inhibited the proliferation of cells containing EGFR exon 20 insertion mutations and C797S mutations. In addition, potent ADCC function against NSCLC cell lines was observed. Significant in vivo anti-tumor efficacy was demonstrated by multiple tumor models of EGFR exon 20 insertion, EGFR C797S mutation, cMET amplification, and cMET exon 14 skipping mutation. Conclusions: GB263T is a novel tri-specific antibody that exhibited robust anti-tumor activity. The preclinical data indicate that GB263T has great potential to become an effective therapeutics in the treatment of NSCLC. Citation Format: Qinglin Du, Wengang Zeng, Xueyan Yang, Liwen Liang, Xueqin Li, Yan Li, Yiqi Cao, Zongjun Xia, Jing Zhang, Qian Ding, Shuhua Han. Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB538.
Abstract 527: A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™
Authors: Cécile Jovelet, Myrtille Remy, Mylene Menanteau, Doug White, Douglas Horejsh, Allison Mallory
Journal: Cancer Research (2022)

Abstract Circulating cell free DNA (cfDNA) extracted from liquid biopsy samples have become established sample types for characterizing oncology targets. Currently, there are several extraction protocols and genomic platforms for researchers to select when interrogating genetic information. The focus of this work was to identify a flexible method for sample extraction that seamlessly integrates into a straightforward and sensitive genetic analysis workflow from plasma samples. Here, we present a workflow combining the Maxwell RSC system for automated cfDNA extraction and Crystal Digital PCR on the naica system for ultrasensitive high-plex detection from liquid biopsy samples of EGFR mutations in non-small cell lung cancer (NSCLC) and PIK3CA mutations and HER2 amplification in breast cancer. By bridging sample extraction with the Maxwell RSC system and high-plex digital PCR with the 6-color naica® system, we detected with high sensitivity and precision 32 common and rare somatic EGFR mutations in exons 18, 19, 20, and 21, representing more than 90% of EGFR mutations described in NSCLC. Furthermore, following the same extraction and sample testing workflow, we simultaneously detected a set of PIK3CA mutations and HER2 amplification from cfDNA samples. This proof-of-concept workflow creates the foundation for further development of streamlined sample-to-answer protocols that will better assist cancer researchers across the biomarker testing landscape. Citation Format: Cécile Jovelet, Myrtille Remy, Mylene Menanteau, Doug White, Douglas Horejsh, Allison Mallory. A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 527.
Epidemiology and Outcomes of SARS-CoV-2 Infection or Multisystem Inflammatory Syndrome in Children vs Influenza Among Critically Ill Children
Authors: Steven L. Shein, Christopher L. Carroll, Kenneth E. Remy, Colin M. Rogerson, Casey K. McCluskey, Anna Lin, Alexandre T. Rotta
Journal: JAMA Network Open (2022)

This cohort study compares the epidemiology and outcomes of patients in the pediatric intensive care unit with SARS-CoV-2–related disease during the first 15 months of the COVID-19 pandemic vs children with critical influenza prior to the pandemic.
Abstract 3943: Discovery of a novel menin-MLL inhibitor for potential treatment of MLLr leukemias and NPM1c AML
Authors: Taishan Hu, Zhilin Deng, Honghai Li, Xiaochu Ma, Quanrong Shen, Lei Zhang, Peihua Sun, Ye Hua, Byran Huang
Journal: Cancer Research (2022)

Abstract Rearrangement of the mixed lineage leukemia (MLL) gene occurs in up to 10% of acute leukemias and is particularly prevalent in infant acute leukemias (~80% of infant ALL cases). MLL-rearranged (MLLr) leukemia is one of the high-risk types of leukemia with aggressive nature, resistance to therapy, and high frequency of early relapse, and currently there are no targeted therapies for its treatment. So, there is huge unmet medical needs for MLLr leukemias. The protein protein interaction (PPI) between menin and MLLr is critical to the pathogenesis of MLLr-driven leukemias by deregulation of the HOXA and MEIS1 genes. It has been demonstrated by both preclinical and clinical studies that blockage of this PPI with menin inhibitors has potential therapeutic effects on MLLr associated acute leukemias. NPM1 mutation (NMP1c) is a frequently mutated gene found in AML, and NMP1 mutated AML depends on menin-MLL interaction for leukemogenesis. Given the fact that wild type MLL and MLLr have similar leukemogenesis-driven target genes like HOXA and MEIS1, as well as the same binding pocket on menin, it was therefore conceived that menin inhibitor could be useful to the treatment of NPM-mutated AML, which was again supported by both preclinical and clinical data. Herein, we would like to report the discovery of our proprietary menin inhibitor. Taking advantage of a couple of key interactions with menin protein, our compounds has relatively low molecular weight for a challenging PPI target, however, demonstrated comparable to or even better potency than those menin inhibitors in clinical trials. Besides in vitro pharmacology data, the DMPK, PK/PD and in vivo efficacy in animal model will be discussed too. Citation Format: Taishan Hu, Zhilin Deng, Honghai Li, Xiaochu Ma, Quanrong Shen, Lei Zhang, Peihua Sun, Ye Hua, Byran Huang. Discovery of a novel menin-MLL inhibitor for potential treatment of MLLr leukemias and NPM1c AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3943.
Inhibition of Sympathetic Activation by Delivering Calcium Channel Blockers from a 3D Printed Scaffold to Promote Bone Defect Repair
Authors: Shikai Li, Zhihui Li, Jin Yang, Yujie Ha, Xiaojun Zhou, Chuanglong He
Journal: Advanced Healthcare Materials (2022)

Abstract Enhancing osteogenesis by promoting neural network reconstruction and neuropeptide release is considered to be an attractive strategy for repairing of critical size bone defects. However, traumatic bone defects often activate the damaged sympathetic nervous system (SNS) in the defect area and release excessive catecholamine to hinder bone defect repair. Herein, a 3D printed scaffold loaded with the calcium channel blocker‐nifedipine is proposed to reduce the concentration of catecholamine present in the bone defect region and to accelerate bone healing. To this end, nifedipine‐loaded ethosome and laponite are added into a mixed solution containing sodium alginate, methacrylated gelatin, and bone mesenchymal stem cells (BMSCs) to prepare a cell‐laden scaffold using 3D bioprinting. The released nifedipine is able to close the calcium channels of nerve cells, thereby blocking sympathetic activation and ultimately inhibiting the release of catecholamine by sympathetic nerve cells, which further promotes the osteogenic differentiation and migration of BMSCs, inhibits osteoclastogenesis in vitro, and effectively improves bone regeneration in a rat critical‐size calvarial defect model. Therefore, the results suggest that sustained release of nifedipine from the scaffold can effectively block SNS activation, providing promising strategies for future treatment of bone defects.